A large but inconclusive body of evidence implicates the role of biogenic amines in the biology of depression and in the mechanism of action of antidepressant drugs. Neurochemical and pharmacological data derived from acute drug effects constitute the bulk of evidence. However, in clinical practice, the efficacy of these agents is slow in developing and requires prolonged periods of treatment. This consideration focuses on the relevance of the study of chronic effects of antidepressants. We propose to study the effects of long-term administration of MAO inhibitors, tricyclic antidepressants, chlorpromazine, and some antihistamines that have been shown to have antidepressant potential on the basis of preclinical pharmacology. The effects of these drugs on the synthesis, uptake, release and catabolism, of the biogenic amines (norepinephrine, dopamine, serotonin, and acetylcholine) and the enzymes invovled in their syntheses and catabolism as well as their effects on the availability of tryptophan for brain serotonin synthesis, will be investigated. The evaluation of neurochemical and pharmacological effects of long-term administration of these psychoactive agents will aid (1) in finding a unifying concept for the antidepressant action of these agents and, (2) in postulating on the underlying defect in pathological depression and, (3) in improving the basis of prediction of clinical activity of antidepressant drugs.